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1. This study was performed in order to determine whether the blockade of sympathetic vasoconstriction in anaesthetized dogs by phentolamine is due to the antagonist action of the drug at postjunctional adrenoceptors, or is due to depression of neurotransmitter release by an agonist action at prejunctional adrenoceptors. 2. In dogs made areflexic by ganglion blockade with hexamethonium, phentolamine (0.5 mg i.a. or 0.5 mg kg-1 i.v.) elevated or did not affect femoral blood flow. By contrast, clonidine (0.5-2.5 nmol, i.a.) produced femoral vasoconstriction, which was attenuated by prior administration of phentolamine. 3. Prior blockade of prejunctional alpha 2-adrenoceptors with yohimbine (30 micrograms kg-1, i.v.) did not reduce the blocking effect of phentolamine (0.5 mg kg-1, i.v.) on neurogenic vasoconstriction. 4. The results indicate that, in anaesthetized dogs, phentolamine lacks appreciable agonist activity at either prejunctional or postjunctional alpha 2-adrenoceptors. The blockade of neurogenic responses by phentolamine is therefore likely to be due to postjunctional adrenoceptor blockade.

1 In chloralose-anaesthetized dogs pretreated with guanethidine and pancuronium, electrical stimulation (0.2 to 5 Hz) of the peripheral end of the cut tibial nerve caused a frequency-dependent increase in femoral blood flow which was restricted to the paw pads. 2 This neurogenic vasodilatation was not attenuated by atropine, mepyramine plus burimamide, indomethacin or propranolol. It was, however, attenuated in a dose-dependent manner by intra-arterial administration of the dopamine receptor antagonist, ergometrine (0.05 to 0.5 mg). 3 The effect of ergometrine could not be explained by non-specific effects on axonal conduction or transmission or by vasospasm of the blood vessels of the paw-pads. 4 In dogs with intact tibial nerves, a pharmacologically similar dilator response localized to the paw-pads could be elicited by electrical stimulation of loci in the ipsilateral diencephalon and midbrain. This response was not due to inhibition of adrenergic vasomotor tone and was abolished by systemic ganglion blockade or by tibial nerve section as well as by femoral arterial administration of ergometrine. 5 It is suggested that the vasculature of the canine paw pads is innervated by a population of autonomic axons which utilize dopamine or a related substance as a transmitter substance and activation of which causes vasodilation.

1 In the isolated vas deferens of the guinea-pig, contractile responses to adrenergic nerve stimulation at 2 Hz were depressed by exogenous dopamine (5 microM) and this effect was abolished in the presence of phentolamine (0.3 microM), suggesting that it was due to an agonist action of dopamine on alpha-adrenotors. 2 The depression by dopamine (5 microM) of contractile responses to nerve stimulation was correlated with reduction in amplitude of single excitatory junction potentials (e.j.ps) evoked by nerve stimulation, but not with depression of spontaneous junction potentials. 3 By contrast, during repetitive nerve stimulation at 1 Hz the depressant effect of dopamine on e.j.p. amplitude became less pronounced, due to the amount of facilitation being greater than that occurring under control conditions in the same cell. 4 The alpha-adrenoceptor antagonist, phentolamine (10 microM), also increased the amount of facilitation during repetitive nerve stimulation. 5 In the presence of phentolamine (10 microM), the depressant effect of dopamine (5 microM) on single e.j.ps was abolished but its enhancing effect on facilitation was not reduced. 6 It is suggested that the enhancement of facilitation during repetitive stimulation by both dopamine and phentolamine is independent of their actions on presynaptic alpha-adrenoceptors.